OVERALL ABSTRACT Interactions between a genetically susceptible host?s mucosal immune system, epithelial barrier and enteric microbiota contribute to the pathogenesis of human inflammatory bowel diseases (IBD). Solving the pathogenesis of IBD and ultimately curing and preventing these chronic, debilitating conditions depend on innovative use of experimental animal models and translational research in human tissue samples to better understand functional, mechanistic interactions between mucosal immune regulation, epithelial responses and enteric microbes that determine intestinal homeostasis vs inflammation. Evidence from human IBD supports the hypothesis that inflammation results from overly aggressive T cell responses to a subset of intestinal microbiota in genetically susceptible hosts with defective mucosal barrier function. Our major objectives of this revised competing renewal are to apply multidisciplinary, mechanistic translational approaches to identify molecular factors and bacterial species that mediate immunologic and epithelial homeostasis and determine how loss of these protective mechanisms result in IBD. Our overall two-part hypothesis is: (i) Bidirectional interactions between intestinal microbial subsets and adaptive (T and B cell) immune and epithelial signaling pathways maintain mucosal homeostasis and (ii) these immune, epithelial pathways and microbial profiles predict disease outcomes and identify clinically relevant subsets of IBD patients. Our translational studies focus on ?mucosal defense?, involving microbial ?crosstalk,? and immune-epithelial interactions. This Program Project addresses basic and translational aspects of these interactions and how they impact clinical IBD heterogeneity. We will test our hypotheses through two overarching aims that link four independent yet intricately integrated projects and two cutting-edge cores. Aim 1: Establish how normal mucosal immune-microbial interactions promote mucosal homeostasis and prevent chronic intestinal inflammation. Aim 2: Use integrative transcriptomics and microbial profiling to molecularly phenotype IBD subsets. This Program Project capitalizes on interactions among multidisciplinary investigators with extensive expertise in microbiology, mucosal immunology, metabolomics, genomics, computational biology and clinical IBD. In just 5 years, this integrated group has already improved understanding of mechanisms involved in IBD pathogenesis using refined experimental disease models and how these pathways impact human IBD. Renewal allows this group to advance these studies to improve management of IBD patients in an individualized fashion. 1